Multiphasic contraceptive regimen for oral combination drug formulation of progestin and estrogen

ABSTRACT

A method for contraception includes administering to a female daily, in a fourphasic dosing regimen during a time period of 24 successive days, an oral combination drug formulation of norethindrone acetate and ethinyl estradiol (EE), wherein doses in the second, third and fourth phases of the regimen increase by a predefined dose increment as compared to the corresponding doses administered during the previous phase, wherein the norethindrone acetate dose in the first phase is 1000 mcg, in the second phase is 1125 mcg, in the third phase is 1250 mcg, and in the fourth phase is 1375 mcg, wherein the EE dose in the first phase is 20 mcg, in the second phase is 22.5 mcg, in the third phase is 25 mcg, and in the fourth phase is 27.5 mcg, and wherein the fourphasic dosing regimen is followed by 4 days without norethindrone acetate and EE administration.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 15/926,407 filed on Mar. 20, 2018, now allowed. Theapplication Ser. No. 15/926,407 is a continuation application of U.S.application Ser. No. 15/593,771 filed on May 12, 2017, now U.S. Pat. No.9,925,199, which is a continuation of U.S. application Ser. No.14/301,768 filed on Jun. 11, 2014, now U.S. Pat. No. 9,675,622. Theapplication Ser. No. 14/301,768 is a continuation of InternationalApplication No. PCT/US2012/068235 filed on Dec. 6, 2012, which claimspriority from U.S. Provisional Application No. 61/570,007 filed on Dec.13, 2011. The above-referenced applications are hereby incorporated byreference in their entirety.

TECHNICAL FIELD

The disclosure generally relates to a multiphasic contraceptive dosingregimen in females including administration of an oral combination drugformulation comprising progestin and estrogen with doses of progestinand estrogen gradually increasing between phases of the regimen,provided that the ratio of a daily dose of progestin to a daily dose ofestrogen is maintained at a constant level during the entire dosingperiod.

BACKGROUND

Hormonal combined oral contraceptives (COCs) are administered annuallyto tens of millions of women. There are different types of COCs withvarious combinations of progestins and estrogens. All COCs may beclassified into two categories: monophasic COCs and multiphasic COCs.The most common classes of multiphasic COCs utilize biphasic andtriphasic treatment regimens with 2 and 3 segments (phases) of theactive drug-taking interval (dosing period), respectively.

Most popular multiphasic regimens are developed as triphasic COCs withchanges in hormonal combinations approximately every 7 days within a21-day active drug-taking interval. In some COC brands, the amount ofestrogen changes during such an active drug-taking interval with aconstant progestin dose (e.g., Estrostep®), while in other brands theamount of progestin changes and the amount of estrogen remains the same(e.g., Ortho Tri-Cyclen®, Ortho Tri-Cyclen Lo®, Ortho-Novum 7/7/7®). Inother COC brands, both amounts of progestin and estrogen change duringthe active drug-taking interval with an increase in both progestin andestrogen amounts in comparison to the starting dose (e.g., Triphasil®,Triadene®).

Increased progestin and/or estrogen levels during the dosing periodmimic the hormonal changes occurring in a woman's menstrual cycle. Thedosage increases, particularly close to end of the drug-taking interval,ensure better suppression of ovulation and desirable changes in theendometrium leading to a greater contraceptive efficacy and improvedmenstrual bleeding pattern (cycle control).

Relatively high progestin and/or estrogen levels during the second andthird weeks of the dosing period were proven to be very instrumental inthe reduction of the total exposure to hormonal contraceptives. A goodexample is a transition from a high dose monophasic contraceptive(Ortho-Cyclen®) delivering 250 mcg of norgestimate (NGM) and 35 mcg ofethinyl estradiol (EE) daily to a triphasic regimen with the same dailyEE dose and reduced overall exposure to NGM (180 mcg, 215 mcg and 250mcg in the first, second and third week of the dosing period,respectively). Since relatively higher levels of NGM were delivered whenthey were needed most (during 2^(nd) and 3^(rd) weeks), an adequatecontraceptive efficacy and cycle control were maintained.

Monophasic COCs are often recommended as a first choice for womenstarting COC use.^(1,2) The reason for this is that monophasic COCs havethe same amount of estrogen and progestin throughout the treatmentcycle, and thus they are less likely to cause side effects that stemfrom fluctuating hormone levels. Such estrogen-related side effectsinclude, e.g., bloating, headache, nausea, mastalgia, leukorrhea, andhypertension; and progestin-related side effects include, e.g., moodswings, cyclic mastalgia, depression, fatigue, decreased libido, andweight gain.³

It would be therefore advantageous to provide multiphasic COCs thatresolve the deficiencies of existing multiphasic combined oralcontraceptives.

SUMMARY

As specified above, there is a great need in the art to develop saferhormonal combined oral contraceptives (COCs) which reduce theundesirable side effects of currently used multiphasic COCs. The variousdisclosed embodiments address these and other needs by providing a novelcombined oral contraceptive (COC) regimen comprising administering anoral combination drug formulation comprising progestin and estrogen as amultiphasic dosing regimen with a constant ratio of a daily dose ofprogestin to a daily dose of estrogen during the entire dosing period.The contraceptive regimen of the present embodiments preserves thecontraceptive efficacy of current multiphasic COCs, while reducing theundesirable side effects associated with variability of the hormonelevels.

Specifically, one exemplary embodiment disclosed herein provides amethod of contraception in which a progestin and an estrogen areadministered as an oral combination drug formulation daily for 21-24days as a multiphasic dosing regimen. A multiphasic dosing regimenincludes several (e.g., two to four) phases with the duration of eachphase ranging from 4 to 16 days. The doses of progestin and estrogengradually increase between phases (e.g., with doses of each of theprogestin and estrogen in each subsequent phase of the regimenincreasing by 10%-50% as compared to the corresponding doses of theprogestin and estrogen administered in the immediately preceding phaseof the regimen), provided that the ratio of a daily dose of progestin toa daily dose of estrogen is maintained at a constant level during the21-24 day dosing period.

The constant progestin-to-estrogen ratio employed by the regimen of thedisclosed embodiments ensures a robust balance between hormonalactivities of each component during the entire dosing period. Thisresults in a better safety profile since unopposed increases in druglevels in the systemic circulation of any component lead to a greaterincidence of hormone-related adverse events, (estrogen-related sideeffects such as, e.g., bloating, headache, nausea, mastalgia,leukorrhea, and hypertension; or progestin-related side effects such as,e.g., mood swings, cyclic mastalgia, depression, fatigue, decreasedlibido, and weight gain). A gradual increase in both progestin andestrogen daily doses between phases of the multiphasic dosing regimen ofthe disclosed embodiments can improve contraceptive efficacy and cyclecontrol when compared to low-dose formulations serving as starting dosesof the currently used multiphasic dosing regimens. The regimensdisclosed herein also result in a reduced total exposure to progestinand estrogen during the entire dosing period and better safety profilewhen compared to a high-dose formulation serving as final doses of thecurrently used multiphasic dosing regimens.

Non-limiting examples of oral drug formulations that are useful in thedisclosed method include, but are not limited to, an oral tablet, anoral capsule and an oral caplet. In all embodiments, one of the agentsis a progestin. Non-limiting examples of useful progestins include, butare not limited to, norgestrel, levonorgestrel, norethindrone,norethindrone acetate norethisterone, norgestimate, medroxyprogesterone,desogestrel, gestodene, dienogest, nestorone, nomegestrol, drospirenone,trimegestone, chlormadinone, cyproterone, and therapeutically acceptablesalts or derivatives thereof. In all embodiments, another agent that canbe utilized is an estrogen. Non-limiting examples of useful estrogensinclude, e.g., ethinyl estradiol, mestranol, estradiol, andtherapeutically acceptable salts or derivatives thereof.

The various disclosed embodiments may be applied to any multiphasicregimen with any number of distinct phases within a dosing period, andwith any duration of a dosing period ranging from a typical 21-daydosing period to a 24-day dosing period.

The various disclosed embodiments are applicable to anyprogestin/estrogen combinations which are useful for contraception. In apreferred embodiment, the multiphasic oral contraceptive containslevonorgestrel (LNG) and ethinyl estradiol (EE). The monophasicformulations of these compounds (100 mcg of LNG in combination with 20mcg of EE and 150 mcg of LNG in combination with 30 mcg of EE) have beentested in numerous clinical trials. The trials established an acceptableLNG-to-EE ratio (5:1) and determined minimal therapeutically effectivedoses of LNG and EE.⁵ This ratio provides experimental basis for anefficacious and safe multiphasic LNG/EE contraceptive regimen.

In another embodiment, the multiphasic LNG/EE COC provides highercontraceptive efficacy and better cycle control when compared to alow-dose monophasic LNG/EE contraceptive regimen. The multiphasic LNG/EECOC also provides better safety profile when compared to a high-dosemonophasic LNG/EE contraceptive regimen. Specific examples of therecommended multiphasic LNG/EE regimens are presented in the followingsections.

While the exact doses for each drug useful in the method may bedetermined in clinical trials, a safe and efficacious multiphasic oralcontraceptive formulation with a robust balance between hormonalactivities of each component is a novel method of combined oralcontraception. A balanced multiphasic regimen covering 21-24 days ofactive drug-taking is a novel method as well.

In conjunction with the above methods, certain disclosed embodimentsprovide contraceptive kits and packages adapted for successive dailyoral administration of the progestin/estrogen formulations at dailydoses and following multiphasic regimens described herein. Non-limitingexamples of useful kits are provided in the section, below.

DETAILED DESCRIPTION

It is important to note that the embodiments disclosed herein are onlyexamples of the many advantageous uses of the innovative teachingsherein. In general, statements made in the specification of the presentapplication do not necessarily limit any of the various claimedembodiments. Moreover, some statements may apply to some inventivefeatures but not to others. In general, unless otherwise indicated,singular elements may be in plural and vice versa with no loss ofgenerality.

In one embodiment, a method of contraception in which a progestin (alsocommonly referred to as progestogen) and an estrogen are administered toa female as an oral combination drug formulation. In an embodiment, theoral combination drug formulation is administered daily for 21-24successive days as a multiphasic dosing regimen consisting of several(e.g., two to four) phases with the duration of each phase ranging from4 to 16 days. The female treated by the disclosed formulation may be ina childbearing age.

The regimen disclosed herein can be used, for example, as a 28-day“treatment period” with the number of days of active drug taking rangingfrom 21 to 24 (“dosing period”) followed by 4 to 7 days withoutprogestin and estrogen (or any other contraceptive steroids)administration.

In all embodiments disclosed herein there are at least two differentdoses of each drug administered within the 21-24 day dosing period withthe doses of a progestin and estrogen gradually increasing betweenphases (e.g., with doses of each of progestin and estrogen in eachsubsequent phase increasing by 10%-50% as compared to the correspondingdoses administered during the immediately preceding phase), providedthat the ratio of a daily dose of progestin to a daily dose of estrogenis maintained at a constant level during the entire dosing period.

According to the disclosed embodiments there are two to four differentphases of the multiphasic dosing regimens with duration of each phaseranging from 4 to 16 days.

In one embodiment, the multiphasic (triphasic) dosing regimen consistsof 21 days of dosing period, with the first 7 days at the lowest dailydoses of the progestin and estrogen; the next 7 days at the intermediatedaily doses of the progestin and estrogen; and the last 7 days at thehighest daily doses of the progestin and estrogen, which dosing periodis followed by 7 days without progestin and estrogen administration.

In another embodiment, the multiphasic (biphasic) dosing regimenconsists of 21 days of dosing period, with the first 11 days at thelower daily doses of the progestin and estrogen; the next 10 days at thehigher daily doses of the progestin and estrogen, which dosing period isfollowed by 7 days without progestin and estrogen administration.

In another embodiment, the multiphasic (biphasic) dosing regimenconsists of 21 days of dosing period, with the first 14 days at thelower daily doses of the progestin and estrogen; the next 7 days at thehigher daily doses of the progestin and estrogen, which dosing period isfollowed by 7 days without progestin and estrogen administration.

In yet another embodiment, the multiphasic (triphasic) dosing regimenconsists of 24 days of dosing period, with the first 8 days at thelowest daily doses of the progestin and estrogen, the next 8 days at theintermediate daily doses of the progestin and estrogen, and the last 8days at the highest daily doses of the progestin and estrogen, whichdosing period is followed by 4 days without progestin and estrogenadministration.

The oral combination drug formulations are preferably administered tofemales one time per day.

The first dose of the disclosed oral combination drug formulation can beadministered, e.g., within 1-7 days after the onset of a menstrualperiod.

Non-limiting examples of oral drug formulations useful in the disclosedmethod include, for example, an oral tablet, an oral capsule, and anoral caplet.

In all embodiments, one of the active agents in the oral combinationdrug formulation is a progestin. Non-limiting examples of usefulprogestins include, for example, norgestrel, levonorgestrel,norethindrone, norethindrone acetate, norethisterone, norgestimate,medroxyprogesterone, desogestrel, gestodene, dienogest, nestorone,nomegestrol, drospirenone, trimegestone, chlormadinone, cyproterone, andtherapeutically acceptable salts or derivatives thereof.

In one embodiment, the progestin is levonorgestrel (LNG). In oneembodiment, the dose of LNG ranges from 100 mcg to 150 mcg per oralcombination drug formulation.

In another embodiment, the progestin is norethindrone acetate. In oneembodiment, the dose of norethindrone acetate ranges from 1000 mcg to1500 mcg per oral combination drug formulation.

In all embodiments, one of the active agents in the oral combinationdrug formulation is an estrogen. Non-limiting examples of usefulestrogens include, e.g., ethinyl estradiol, mestranol, estradiol, andtherapeutically acceptable salts or derivatives thereof.

In one embodiment, the estrogen is ethinyl estradiol (EE). In oneembodiment, the dose of EE ranges from 20 mcg to 30 mcg per oralcombination drug formulation.

In one embodiment, the ratio of the daily dose of progestin to the dailydose of estrogen ranges from 5:1 to 50:1.

In a preferred embodiment, the ratio of the daily dose of LNG to thedaily dose of EE is 5:1.

In another preferred embodiment, the ratio of the daily dose ofnorethindrone acetate to the daily dose of EE is 50:1.

In a preferred embodiment, (i) 100 mcg of LNG in combination with 20 mcgof EE is administered daily during the first 7 days of the 21-day dosingperiod (cycle days 1-7), (ii) 125 mcg of LNG in combination with 25 mcgof EE is administered daily during the next 7 days of the 21-day dosingperiod (cycle days 8-14), and (iii) 150 mcg of LNG in combination with30 mcg of EE is administered daily during the last 7 days of the 21-daydosing period (cycle days 15-21), followed by 7 days without progestinand estrogen administration.

In another preferred embodiment, (i) 112.5 mcg of LNG in combinationwith 22.5 mcg of EE is administered daily during the first 7 days of the21-day dosing period (cycle days 1-7), (ii) 125 mcg of LNG incombination with 25 mcg of EE is administered daily during the next 7days of the 21-day dosing period (cycle days 8-14), and (iii) 137.5 mcgof LNG in combination with 27.5 mcg of EE is administered daily duringthe last 7 days of the 21-day dosing period (cycle days 15-21), followedby 7 days without progestin and estrogen administration.

In yet another embodiment, (i) 100 mcg of LNG in combination with 20 mcgof EE is administered daily during the first 11 days of the 21-daydosing period (cycle days 1-11), and (ii) 150 mcg of LNG in combinationwith 30 mcg of EE is administered daily during the next 10 days of the21-day dosing period (cycle days 12-21), followed by 7 days withoutprogestin and estrogen administration.

In a further embodiment, (i) 100 mcg of LNG in combination with 20 mcgof EE is administered daily during the first 14 days of the 21-daydosing period (cycle days 1-14), and (ii) 150 mcg of LNG in combinationwith 30 mcg of EE is administered daily during the next 7 days of the21-day dosing period (cycle days 15-21), followed by 7 days withoutprogestin and estrogen administration.

In another embodiment, (i) 100 mcg of LNG in combination with 20 mcg ofEE is administered daily during the first 8 days of the 24-day dosingperiod (cycle days 1-8); (ii) 125 mcg of LNG in combination with 25 mcgof EE is administered daily during the next 8 days of the 24-day dosingperiod (cycle days 9-16), and (iii) 150 mcg of LNG in combination with30 mcg of EE is administered daily during the next 8 days of the 24-daydosing period (cycle days 17-24), followed by 4 days without progestinand estrogen administration.

In another embodiment, (i) 1000 mcg of norethindrone acetate incombination with 20 mcg of EE is administered daily during the first 7days of the 21-day dosing period (cycle days 1-7), (ii) 1250 mcg ofnorethindrone acetate in combination with 25 mcg of EE is administereddaily during the next 7 days of the 21-day dosing period (cycle days8-14), and (iii) 1500 mcg of norethindrone acetate in combination with30 mcg of EE is administered daily during the last 7 days of the 21-daydosing period (cycle days 15-21), followed by 7 days without progestinand estrogen administration.

In yet another embodiment, (i) 1125 mcg of norethindrone acetate incombination with 22.5 mcg of EE is administered daily during the first 7days of the 21-day dosing period (cycle days 1-7), (ii) 1250 mcg ofnorethindrone acetate in combination with 25 mcg of EE is administereddaily during the next 7 days of the 21-day dosing period (cycle days8-14), and (iii) 1375 mcg of norethindrone acetate in combination with27.5 mcg of EE is administered daily during the last 7 days of the21-day dosing period (cycle days 15-21), followed by 7 days withoutprogestin and estrogen administration.

In a further embodiment, (i) 1000 mcg of norethindrone acetate incombination with 20 mcg of EE is administered daily during the first 11days of the 21-day dosing period (cycle days 1-11), and (ii) 1500 mcg ofnorethindrone acetate in combination with 30 mcg of EE is administereddaily during the next 10 days of the 21-day dosing period (cycle days12-21), followed by 7 days without progestin and estrogenadministration.

In another embodiment, (i) 1000 mcg of norethindrone acetate incombination with 20 mcg of EE is administered daily during the first 14days of the 21-day dosing period (cycle days 1-14), and (ii) 1500 mcg ofnorethindrone acetate in combination with 30 mcg of EE is administereddaily during the next 7 days of the 21-day dosing period (cycle days15-21), followed by 7 days without progestin and estrogenadministration.

In yet another embodiment, (i) 1000 mcg of norethindrone acetate incombination with 20 mcg of EE is administered daily during the first 8days of the 24-day dosing period (cycle days 1-8); (ii) 1250 mcg ofnorethindrone acetate in combination with 25 mcg of EE is administereddaily during the next 8 days of the 24-day dosing period (cycle days9-16), and (iii) 1500 mcg of norethindrone acetate in combination with30 mcg of EE is administered daily during the next 8 days of the 24-daydosing period (cycle days 17-24), followed by 4 days without progestinand estrogen administration.

The disclosed embodiments also provided contraceptive kits and packagesadapted for successive daily oral administration of theprogestin/estrogen formulations at daily doses and following multiphasicregimens described herein.

In one embodiment, a multiphasic contraceptive kit adapted forsuccessive daily oral administration is provided. The kit comprises: (i)21-24 separate daily dosage units, each dosage unit comprises aprogestin and an estrogen and the ratio of the dose of progestin to thedose of estrogen is the same for all dosage units, and the dosage unitsare divided into two to four phases with 4 to 16 dosage units in eachphase, the doses of each of the progestin and estrogen in eachsubsequent phase are increased by 10%-50% as compared to thecorresponding doses of the progestin and estrogen in the immediatelypreceding phase; and (ii) optionally comprising 4-7 daily dosage unitshaving no contraceptive steroids, and (iii) optionally comprisinginstructions for use.

In one specific embodiment, the multiphasic contraceptive kit adaptedfor successive daily oral administration is provided. The kit comprises:(i) 21 separate daily dosage units divided into three phases. The firstphase contains 7 dosage units, each dosage unit comprising 100 mcg oflevonorgestrel (LNG) and 20 mcg of ethinyl estradiol (EE); the secondphase contains 7 dosage units, each dosage unit comprising 125 mcg ofLNG and 25 mcg of EE, and the third phase contains 7 daily dosage units,each dosage unit comprising 150 mcg of LNG and 30 mcg of EE, and (ii)optionally comprises 7 daily dosage units having no contraceptivesteroids, and (iii) optionally comprises instructions for use.

In another specific embodiment, the multiphasic contraceptive kitadapted for successive daily oral administration is provided. The kitcomprises: (i) 21 separate daily dosage units divided into two phases.The first phase contains 11 dosage units, each dosage unit comprising100 mcg of levonorgestrel (LNG) and 20 mcg of ethinyl estradiol (EE);and the second phase contains 10 dosage units, each dosage unitcomprising 150 mcg of LNG and 30 mcg of EE, and (ii) optionallycomprises 7 daily dosage units having no contraceptive steroids, and(iii) optionally comprises instructions for use.

In yet another specific embodiment, the multiphasic contraceptive kitadapted for successive daily oral administration is provided. The kitcomprises: (i) 21 separate daily dosage units divided into two phases.The first phase contains 14 dosage units, each dosage unit comprising100 mcg of levonorgestrel (LNG) and 20 mcg of ethinyl estradiol (EE);and the second phase contains 7 dosage units, each dosage unitcomprising 150 mcg of LNG and 30 mcg of EE, and (ii) optionallycomprises 7 daily dosage units having no contraceptive steroids, and(iii) optionally comprises instructions for use.

In another embodiment, the multiphasic contraceptive kit adapted forsuccessive daily oral administration is provided. The kit comprises: (i)24 separate daily dosage units divided into three phases. The firstphase contains 8 dosage units, each dosage unit comprising 100 mcg oflevonorgestrel (LNG) and 20 mcg of ethinyl estradiol (EE); the secondphase contains 8 dosage units, each dosage unit comprising 125 mcg ofLNG and 25 mcg of EE, and the third phase contains 8 daily dosage units,each dosage unit comprising 150 mcg of LNG and 30 mcg of EE, and (ii)optionally comprises 4 daily dosage units having no contraceptivesteroids, and (iii) optionally comprises instructions for use.

In yet another embodiment, the multiphasic contraceptive kit adapted forsuccessive daily oral administration is provided. The kit comprises: (i)21 separate daily dosage units divided into three phases. The firstphase contains 7 dosage units, each dosage unit comprising 1000 mcg ofnorethindrone acetate and 20 mcg of ethinyl estradiol (EE); the secondphase contains 7 dosage units, each dosage unit comprising 1250 mcg ofnorethindrone acetate and 25 mcg of EE, and the third phase contains 7daily dosage units, each dosage unit comprising 1500 mcg ofnorethindrone acetate and 30 mcg of EE, and (ii) optionally comprises 7daily dosage units having no contraceptive steroids, and (iii)optionally comprises instructions for use.

In a further embodiment, the multiphasic contraceptive kit adapted forsuccessive daily oral administration is provided. The kit comprises: (i)21 separate daily dosage units divided into two phases. The first phasecontains 11 dosage units, each dosage unit comprising 1000 mcg ofnorethindrone acetate and 20 mcg of ethinyl estradiol (EE); and thesecond phase contains 10 dosage units, each dosage unit comprising 1500mcg of norethindrone acetate and 30 mcg of EE, and (ii) optionallycomprises 7 daily dosage units having no contraceptive steroids, and(iii) optionally comprises instructions for use.

In another embodiment, the multiphasic contraceptive kit adapted forsuccessive daily oral administration is provided. The kit comprises: (i)21 separate daily dosage units divided into two phases. The first phasecontains 14 dosage units, each dosage unit comprising 1000 mcg ofnorethindrone acetate land 20 mcg of ethinyl estradiol (EE); and thesecond phase contains 7 dosage units, each dosage unit comprising 1500mcg of norethindrone acetate and 30 mcg of EE, and (ii) optionallycomprises 7 daily dosage units having no contraceptive steroids, and(iii) optionally comprises instructions for use.

In yet another embodiment, the multiphasic contraceptive kit adapted forsuccessive daily oral administration is provided. The kit comprises: (i)24 separate daily dosage units divided into three phases. The firstphase contains 8 dosage units, each dosage unit comprising 1000 mcg ofnorethindrone acetate and 20 mcg of ethinyl estradiol (EE); the secondphase contains 8 dosage units, each dosage unit comprising 1250 mcg ofnorethindrone acetate and 25 mcg of EE, and the third phase contains 8daily dosage units, each dosage unit comprising 1500 mcg ofnorethindrone acetate and 30 mcg of EE, and (ii) optionally comprises 4daily dosage units having no contraceptive steroids, and (iii)optionally comprises instructions for use.

The active compounds of the disclosed embodiments can be formulated inan oral combination drug formulation in combination with one or morepharmaceutically acceptable carriers and/or excipients such as, forexample, stabilizers, lubricants, diluents, flavorants, colorants,buffers, and disintegrants. Suitable pharmaceutically acceptablecarriers include any and all conventional solvents (e.g., water,physiological solution, dextrose, glycerol, ethanol, and the like, aswell as combinations thereof), wetting agents, emulgators, buffers,conservants, antioxidants, dispersion media, fillers, solid carriers,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents, as well as other well-known agents which enhance theshelf life or effectiveness of one or more of the active components ofthe composition. Examples of such useful substances can be found, forexample, in the book Remington: the science and practice of pharmacy.Lippincott Williams & Wilkins 2005. Except insofar as any conventionalmedia or agent is incompatible with the active ingredients, use thereofin compositions of the present invention is contemplated.

It will be readily evident to one of ordinary skill that the variousapproaches useful in preparing pharmaceutical formulations, as describedherein, and other approaches known in the art, may be combined in asingle oral combination drug formulation.

Contraceptive kits and packages disclosed herein can be preparedfollowing methods and designs well known in the art with appropriatedaily dosage units (e.g., tablets, capsules, or caplets) arranged in afixed sequence corresponding to various phases of a given administrationregimen. Kits can optionally comprise instructions for use. Also,non-contraceptive dosage units may be optionally included in a kit forthe remaining days of the 28-day cycle. Such non-contraceptive dosageunits may optionally contain an iron supplement (e.g., ferrousfumarate).

The various disclosed embodiments are also described and demonstrated bythe following non-limiting examples. However, the use of these and otherexamples anywhere in the specification is illustrative only and in noway limits the scope and meaning of the disclosed embodiments or of anyexemplified term. Likewise, the disclosed embodiments are not limited toany particular preferred embodiments described here. Indeed, manymodifications and variations of the embodiments described here may beapparent to those skilled in the art upon reading this specification,and such variations can be made without departing from the disclosedembodiments in spirit or in scope. The disclosed embodiments aretherefore to be limited only by the terms of the appended claims alongwith the full scope of equivalents to which those claims are entitled.

The various disclosed embodiments are particularly useful formultiphasic formulations of levonorgestrel (LNG) and ethinyl estradiol(EE). A number of popular COCs (Alesse®, Nordette®, Triphasil®,Seasonique®, Seasonale®, etc) employ these hormones. LNG is alsoadministered as a contraceptive progestin-only pill (Norgeston®), as anemergency contraceptive (Plan B®), as a hormonal agent in theintrauterine contraceptive system (Mirena®), and as a component of themedication developed for the treatment of menopausal symptoms (ClimaraPro®).

While EE is present in an overwhelming majority of other COCs, uniquefeatures of LNG contribute to the popularity of the LNG/EE combined oralcontraceptives. LNG-containing COCs are proven to be efficacious andsafe treatment options for millions of women electing hormonalcontraception. There are huge clinical databases confirmingcontraceptive and non-contraceptive benefits of the LNG/EE COCs.Importantly, LNG is known for the lowest incidence of venousthromboembolism (VTE) when compared to other contraceptive progestins,such as gestodene, desogestrel and drospirenone.⁴

A combination of daily dose of 100 mcg LNG and 20 mcg of EE is approvedin the US (Alesse®, Levlite® and their generic equivalents) and othercountries. This LNG/EE dose can be used as a starting dose to beadministered during the first phase of a multiphasic dosing regimen ofthe disclosed embodiments. Since a relatively greater contraceptiveefficacy and better cycle control with acceptable safety profile areconfirmed for a higher-dose COC containing 150 mcg LNG and 30 mcg of EEalso marketed in the US and other countries (Nordette®, Levlen®,Microgynon® and their generic equivalents), this LNG/EE dose can be usedas a maximal dose to be administered during the last phase of amultiphasic dosing regimen of the disclosed according to someembodiments. The LNG/EE ratio (5:1) which has been established andtested in numerous clinical trials⁵ can be used as a constant ratio of adaily dose of progestin to a daily dose of estrogen during the entiredosing period in one of the regimens of the disclosed according to someembodiments.

As a first non-limiting example, available clinical data for amonophasic formulation of 100 mcg LNG/20 mcg EE suggestless-than-optimal performance of this COC. One study reported rates ofpresumptive ovulation exceeding 20%⁶, i.e., much greater than athreshold of 10% routinely used in the testing of contraceptives.⁷ Inanother clinical study, Pearl Index (a number of pregnancies per 100woman-years of product use) was 1.7 times greater in 100 mcg LNG/20 mcgEE monophasic group when compared to a higher-dose monophasic regimen(150 mcg LNG/30 mcg EE). When the same formulations were administered asa continuous 91-day dosing regimen, pregnancy rates were 2 times greaterin a low-dose group. In both cases, treatment with 100 mcg LNG/20 mcg EEresulted in contraceptive efficacy inferior to any approved combinedoral contraceptive.⁸ Cycle control of the low-dose LNG/EE formulation(as assessed by the incidence of inter-menstrual bleeding) is alsoinferior to most of marketed COCs.⁹

The disclosed embodiments hypothesize that there is a need for anincrease in both progestin and estrogen doses for effectivecontraception and cycle control, while better safety can be provided bymaintaining an optimal constant progestin-to-estrogen ratio during theentire dosing period.

The disclosed embodiment provides a triphasic LNG/EE regimen with thefollowing dosing schedule: (a) 100 mcg of LNG in combination with 20 mcgof EE is administered daily during the first 7 days of the 21-day dosingperiod (cycle days 1-7), (b) 125 mcg of LNG in combination with 25 mcgof EE is administered daily during the next 7 days of the 21-day dosingperiod (cycle days 8-14), and (c) 150 mcg of LNG in combination with 30mcg of EE is administered daily during the next 7 days of the 21-daydosing period (cycle days 15-21). The last 7 days of the treatmentperiod (cycle days 22-28) are contraceptive steroid-free. The total doseof progestin and estrogen per proposed multiphasic regimen is 17% lesswhen compared to a high-dose monophasic LNG/EE COC (Nordette®, Levlen®,Microgynon® and their generic equivalents).

As another non-limiting example, 112.5 mcg of LNG in combination with22.5 mcg of EE is administered daily during the first 7 days of the21-day dosing period (cycle days 1-7), 125 mcg of LNG in combinationwith 25 mcg of EE is administered daily during the next 7 days of the21-day dosing period (cycle days 8-14), and 137.5 mcg of LNG incombination with 27.5 mcg of EE is administered daily during the next 7days of the 21-day dosing period (cycle days 15-21). The last 7 days ofthe treatment period (cycle days 22-28) are contraceptive steroid-free.

As another non-limiting example, 100 mcg of LNG in combination with 20mcg of EE is administered daily during the first 11 days of the 21-daydosing period (cycle days 1-11), 150 mcg of LNG in combination with 30mcg of EE is administered daily during the next 10 days of the 21-daydosing period (cycle days 12-21). The last 7 days of the treatmentperiod (cycle days 22-28) are contraceptive steroid-free.

As yet another non-limiting example, 100 mcg of LNG in combination with20 mcg of EE is administered daily during the first 14 days of the21-day dosing period (cycle days 1-14), 150 mcg of LNG in combinationwith 30 mcg of EE is administered daily during the next 7 days of the21-day dosing period (cycle days 15-21). The last 7 days of thetreatment period (cycle days 22-28) are contraceptive steroid-free.

As yet another non-limiting example, 100 mcg of LNG in combination with20 mcg of EE is administered daily during the first 8 days of the 24-daydosing period (cycle days 1-8), 125 mcg of LNG in combination with 25mcg of EE is administered daily during the next 8 days of the 24-daydosing period (cycle days 9-16), and 150 mcg of LNG in combination with30 mcg of EE is administered daily during the next 8 days of the 24-daydosing period (cycle days 17-24). The last 4 days of the treatmentperiod (cycle days 25-28) are contraceptive steroid-free.

As yet another non-limiting example, the triphasic norethindroneacetate/ethinyl estradiol regimen with the following dosing schedule:(a) 1000 mcg of norethindrone acetate in combination with 20 mcg of EEis administered daily during the first 7 days of the 21-day dosingperiod (cycle days 1-7), (b) 1250 mcg of norethindrone acetate incombination with 25 mcg of EE is administered daily during the next 7days of the 21-day dosing period (cycle days 8-14), and (c) 1500 mcg ofnorethindrone acetate in combination with 30 mcg of EE is administereddaily during the next 7 days of the 21-day dosing period (cycle days15-21). The last 7 days of the treatment period (cycle days 22-28) arecontraceptive steroid-free.

As yet another non-limiting example, 1125 mcg of norethindrone acetatein combination with 22.5 mcg of EE is administered daily during thefirst 7 days of the 21-day dosing period (cycle days 1-7), 1250 mcg ofnorethindrone acetate in combination with 25 mcg of EE is administereddaily during the next 7 days of the 21-day dosing period (cycle days8-14), and 1375 mcg of norethindrone acetate in combination with 27.5mcg of EE is administered daily during the next 7 days of the 21-daydosing period (cycle days 15-21). The last 7 days of the treatmentperiod (cycle days 22-28) are contraceptive steroid-free.

As yet another non-limiting example, 1000 mcg of norethindrone acetatein combination with 20 mcg of EE is administered daily during the first11 days of the 21-day dosing period (cycle days 1-11), 1500 mcg ofnorethindrone acetate in combination with 30 mcg of EE is administereddaily during the next 10 days of the 21-day dosing period (cycle days12-21). The last 7 days of the treatment period (cycle days 22-28) arecontraceptive steroid-free.

As yet another non-limiting example, 1000 mcg of norethindrone acetatein combination with 20 mcg of EE is administered daily during the first14 days of the 21-day dosing period (cycle days 1-14), 1500 mcg ofnorethindrone acetate in combination with 30 mcg of EE is administereddaily during the next 7 days of the 21-day dosing period (cycle days15-21). The last 7 days of the treatment period (cycle days 22-28) arecontraceptive steroid-free.

As yet another non-limiting example, 1000 mcg of norethindrone acetatein combination with 20 mcg of EE is administered daily during the first8 days of the 24-day dosing period (cycle days 1-8), 1250 mcg ofnorethindrone acetate in combination with 25 mcg of EE is administereddaily during the next 8 days of the 24-day dosing period (cycle days9-16), and 1500 mcg of norethindrone acetate in combination with 30 mcgof EE is administered daily during the next 8 days of the 24-day dosingperiod (cycle days 17-24). The last 4 days of the treatment period(cycle days 25-28) are contraceptive steroid-free.

All patents, applications, publications, test methods, literature, andother materials cited herein are hereby incorporated by reference intheir entirety as if physically present in this specification.

REFERENCES

-   ¹Grimes D A., et al. Triphasic versus monophasic oral contraceptives    for contraception. Cochrane Database of Systematic Reviews 2006,    Issue 3. Art. No.: CD003553.-   ²Van Vliet H, et al. Biphasic versus triphasic oral contraceptives    for contraception: a Cochrane review. Human Reproduction (2002) 17    (4): 870-873.-   ³Lalley J J. Oral contraceptives overview. UMHS 2002 July [online].    Accessed at    http://www.med.umich.edu/obgyn/resdir/contraception/OralContLalley.html    (reference on file).-   ⁴Benagiano G, Carrara S, Filippi V. Safety, efficacy and patient    satisfaction with continuous daily administration of    levonorgestrel/ethinylestradiol oral contraceptives. Patient    Preference and Adherence. 2009; 3:131-43.-   ⁵Dando T M and Curran M P. Low dose ethinylestradiol and    levonorgestrel. Drugs 2005; 65 (16): 2299-2306.-   ⁶Pierson R A, et al. Ortho Evra versus oral contraceptives:    follicular development and ovulation in normal cycles and after an    intentional dosing error. Fertil Steril 2003; 80:34-42.-   ⁷Heger-Mahn D., et al. Combined ethinylestradiol/gestodene    contraceptive patch: two-center, open-label study of ovulation    inhibition, acceptability and safety over two cycles in female    volunteers. European Journal of Contraception and Reproductive    Health Care, 9:173-181, 2004.-   ⁸Center for Drug Evaluation and Research. Application Number 21-544.    Seasonale® NDA Medical review; accessed at    http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-544_SEASONALE_Medr_P1.pdf    (reference on file).-   ⁹Center for Drug Evaluation and Research. Application Number 21-241.    Ortho Tri-Cyclen Lo® NDA Medical review; accessed at    http://www.accessdata.fda.gov/drugsatfda docs/nda/2002/021241 S000    ORTH O-TRI-CYCLENE MEDR.pdf (reference on file).

What is claimed is:
 1. A method of contraception in a female,comprising: administering to the female daily, during a time period of24 successive days, an oral combination drug formulation of a progestinand estrogen, wherein the oral combination drug formulation isadministered in a fourphasic dosing regimen comprising a first phase, asecond phase, a third phase, and a fourth phase, wherein the duration ofthe first phase is 6 days, wherein the duration of the second phase is 6days, wherein the duration of the third phase is 6 days, wherein theduration of the fourth phase is 6 days, wherein doses of each of theprogestin and estrogen in the second, third and fourth phases of theregimen increase by a predefined dose increment as compared to thecorresponding doses of the progestin and estrogen administered duringthe previous phases of the regimen, wherein the ratio of a daily dose ofprogestin to a daily dose of estrogen is maintained at a constant levelduring the entire dosing period, wherein the progestin in the oralcombination drug formulation is norethindrone acetate, wherein theestrogen in the oral combination drug formulation is ethinyl estradiol(EE), wherein the oral combination drug formulation is 1000 mcg ofnorethindrone acetate in combination with 20 mcg of EE and isadministered daily during the first phase, wherein the oral combinationdrug formulation is 1125 mcg of norethindrone acetate in combinationwith 22.5 mcg of EE and is administered daily during the second phase,wherein the oral combination drug formulation is 1250 mcg ofnorethindrone acetate in combination with 25.0 mcg of EE and isadministered daily during the third phase, and wherein the oralcombination drug formulation is 1375 mcg of norethindrone acetate incombination with 27.5 mcg of EE and is administered daily during thefourth phase, and wherein the fourphasic dosing regimen is followed by atime period of 4 days without progestin and estrogen administration. 2.The method of claim 1, wherein the oral combination drug formulation isin a form of any one of: an oral tablet, an oral capsule, and an oralcaplet.
 3. A method of contraception in a female, comprising:administering to the female daily, during a time period of 24 successivedays, an oral combination drug formulation of a progestin and estrogen,wherein the oral combination drug formulation is administered in afourphasic dosing regimen comprising a first phase, a second phase, athird phase, and a fourth phase, wherein the duration of the first phaseis 6 days, wherein the duration of the second phase is 6 days, whereinthe duration of the third phase is 6 days, wherein the duration of thefourth phase is 6 days, wherein doses of each of the progestin andestrogen in the second, third and fourth phases of the regimen increaseby a predefined dose increment as compared to the corresponding doses ofthe progestin and estrogen administered during the previous phases ofthe regimen, wherein the ratio of a daily dose of progestin to a dailydose of estrogen is maintained at a constant level during the entiredosing period, wherein the progestin in the oral combination drugformulation is levonorgestrel, wherein the estrogen in the oralcombination drug formulation is ethinyl estradiol (EE), wherein the oralcombination drug formulation is 100 mcg of levonorgestrel in combinationwith 20 mcg of EE and is administered daily during the first phase,wherein the oral combination drug formulation is 112.5 mcg oflevonorgestrel in combination with 22.5 mcg of EE and is administereddaily during the second phase, wherein the oral combination drugformulation is 125 mcg of levonorgestrel in combination with 25.0 mcg ofEE and is administered daily during the third phase, and wherein theoral combination drug formulation is 137.5 mcg of levonorgestrel incombination with 27.5 mcg of EE and is administered daily during thefourth phase, and wherein the fourphasic dosing regimen is followed by atime period of 4 days without progestin and estrogen administration. 4.The method of claim 3, wherein the oral combination drug formulation isin a form of any one of: an oral tablet, an oral capsule, and an oralcaplet.
 5. A method of contraception in a female, comprising:administering to the female daily, during a time period of 21 successivedays, an oral combination drug formulation of a progestin and estrogen,wherein the oral combination drug formulation is administered in afourphasic dosing regimen comprising a first phase, a second phase, athird phase, and a fourth phase, wherein the duration of the first phaseis 5 days, wherein the duration of the second phase is 5 days, whereinthe duration of the third phase is 5 days, wherein the duration of thefourth phase is 6 days, wherein doses of each of the progestin andestrogen in the second, third and fourth phases of the regimen increaseby a predefined dose increment as compared to the corresponding doses ofthe progestin and estrogen administered during the previous phases ofthe regimen, wherein the ratio of a daily dose of progestin to a dailydose of estrogen is maintained at a constant level during the entiredosing period, wherein the progestin in the oral combination drugformulation is levonorgestrel, wherein the estrogen in the oralcombination drug formulation is ethinyl estradiol (EE), wherein the oralcombination drug formulation is 100 mcg of levonorgestrel in combinationwith 20 mcg of EE and is administered daily during the first phase,wherein the oral combination drug formulation is 112.5 mcg oflevonorgestrel in combination with 22.5 mcg of EE and is administereddaily during the second phase, wherein the oral combination drugformulation is 125 mcg of levonorgestrel in combination with 25.0 mcg ofEE and is administered daily during the third phase, and wherein theoral combination drug formulation is 137.5 mcg of levonorgestrel incombination with 27.5 mcg of EE and is administered daily during thefourth phase, and wherein the fourphasic dosing regimen is followed by atime period of 7 days without progestin and estrogen administration. 6.The method of claim 5, wherein the oral combination drug formulation isin a form of any one of: an oral tablet, an oral capsule, and an oralcaplet.